POS1156 PHASE 1 TRIALS OF NOVEL ORAL ENZYME THERAPY (ALLN-346) FOR HYPERURICEMIA &amp; GOUT: SAFETY, PHARMACODYNAMICS, AND LACK OF SYSTEMIC ABSORPTION OF SINGLE AND MULTIPLE ASCENDING DOSES IN HEALTHY VOLUNTEERS
Authors: D. Clark, D. Grujic, C. Tosone, N. Dahl, R. Terkeltaub
Journal: Annals of the Rheumatic Diseases (2022)

Background Currently available therapies for gout in patients with advanced chronic kidney disease (CKD) are either dose-limited or contraindicated due to safety and tolerability concerns. In gout patients with advanced CKD, the intestinal tract becomes the major route of urate elimination, in contrast to healthy people with normal kidney function whose kidneys are the primary route of uric acid excretion. 1. Considering some of the limitations of present urate lowering therapies (ULTs) in gout &amp; CKD and the extra-renal pathway of urate secretion, a new oral therapy with ALLN-346 (engineered urate oxidase) is under development as a non-absorbed, urate specific enzyme, designed to enhance degradation and secretion of urate in the intestinal tract. 2 Objectives To assess safety and tolerability and evidence for the lack of systemic absorption at various dose levels of ALLN-346 in normal healthy volunteers (NHV) up to 7 days. Methods Two randomized, double-blind Phase 1 studies of ALLN-346 or placebo were conducted in adult NHV in a domicile setting; a single-ascending dose (SAD) study of 3 doses on a single day of dosing, and a multiple ascending dose (MAD) study of 2 doses during 7 days ( NCT04236219 and NCT04829435 , respectively). In the SAD study, subjects received 3 ascending doses of ALLN-346 (3 capsules,6 capsules, and 6 capsules administered twice, or placebo) and were randomized 3:1 (ALLN-346:placebo, n=24). In the MAD study, subjects received 3 (Cohort A) or 5 (Cohort B) of ALLN-346 capsules or placebo (2:1 randomization, n=18) administered orally 3 times daily for 7 days. To assess possible ALLN-346 absorption, a specific ELISA and uricase potency assay were used on PK serum samples collected from all subjects in both studies pre-dose and at intervals post dose. Results In both studies, all randomized subjects completed treatment with 100% compliance. ALLN-346 was well-tolerated, with no serious adverse events (AE) and with no clinically significant safety signals across all cumulative doses. Clinical and laboratory parameters revealed no clinically significant safety signals among all cumulative dosing cohorts across hematology, serum biochemistry, vital signs, or ECGs. The majority of reported AEs were mild with no pattern of differences between ALLN-346 and placebo. No evidence of systemic absorption of ALLN-346 was seen, as confirmed by both ELISA and by uricase potency assay of all PK serum samples from all subjects from SAD (n=240) and MAD (n=324). Conclusion ALLN-346, a new oral enzyme therapy in development for the treatment of hyperuricemia and gout in advanced CKD was well tolerated. Consistent with its mechanism of action, no evidence of systemic absorption was demonstrated. Furtherstudies in hyperuricemia patients with gout and CKD are underway. References [1]Sorensen BL. Role of the intestinal tract in the elimination of uric acid. Arthritis and Rheumatism, vol 8, part5 1965 [2]Pierzynowska K, Deshpande A, Mosiichuk N, et al. Oral Treatment with an Engineered Uricase, ALLN-346, Reduces Hyperuricemia, and Uricosuria in Urate Oxidase-Deficient Mice. Front Med (Lausanne). 2020 Nov 24;7:569215. Disclosure of Interests David Clark Shareholder of: Allena, Employee of: Allena, Danica Grujic Shareholder of: Allena, Employee of: Allena, Christine Tosone Shareholder of: Allena, Employee of: Allena, Naomi Dahl Shareholder of: AbbVie (shares), Allena (options), Employee of: Allena, Robert Terkeltaub Consultant of: Allena, SOBI, Astra-Zeneca, Fortress, Grant/research support from: Astra-Zeneca